The hippocampus is one of the most extensively studied brain regions. The popularity of this structure derives from four considerations-it is important in major clinical disorders; its architecture is convenient, relative to other cortical areas, for experimental analysis; it appears to play an essential role in "cognitive" forms of learning and/or memory; and its synapses exhibit long-term potentiation (LTP), currently the leading candidate mechanism for rapid learning in mammals. Within the hippocampus, the neurophysiology of synapses in region CA3 region is the least understood. The granule cells of the dentate gyrus provide an important synaptic input to region CA3. The granule cell's mossy-fiber (mf) synaptic input is unusual and interesting for several reasons-they are among the largest synapses in the brain; they contain dynorphin and high concentrations of zinc; and they display a form of LTP that is different from the kind that is most often studied in other regions of the hippocampus and neocortex. The induction of mf LTP is not dependent on activation of N-methyl-d-aspartate (NMDA) receptors. We now know that NMDA receptor-independent LTP is not unique to the mf synapses, but also exists in synapses of other brain regions, such las the amygdala. The mf synapses offer a number of unique experimental advantages, which we will develop and exploit. State-of-the-art experimental and analytical methods will be used to examine the microphysiology of mf synapses and to test several hypotheses about the mechanisms underlying mf LTP induction and expression. The methods include whole-cell recordings of synaptic currents; quantal analysis; optical measurements of synaptic microstructure, calcium transients, and vesicle recycling; and compartmental modelling of mf synapses and CA3 pyramidal neurons. The results will provide a firm understanding of synaptic signalling and plasticity in the mf synapses, furnishing a key piece in the larger puzzle of how the hippocampal circuitry processes and stores information. This knowledge will be relevant to other brain regions, where comparable experiments would be impracticable.